Drug addiction is characterized by repeating cycles of drug intoxication, withdrawal, and relapse. The greatest challenge in the treatment of addiction is the prevention of relapse to further drug-seeking and drug-taking behaviors. The negative mood state produced by drug withdrawal, including heightened states of anxiety and anhedonia, is a major contributor to relapse. Relapse is also facilitated by exposure to external stressors. This is an application for a competitive renewal of our research project that investigates the impact of chronic exposure to cocaine on the delta opioid receptor system. During the prior award period, we have shown that acute withdrawal from repeated cocaine administration results in increases in anxiety- and depression-like behaviors in a rat model and these behavioral effects are accompanied by a desensitization of delta opioid receptor signaling. Delta opioid receptor agonists were shown to be effective anxiolytic agents under both baseline conditions and during cocaine withdrawal. The important role of delta opioid receptors in anxiety was further demonstrated by the ability of delta opioid receptor agonists to attenuate stress-induced anxiety when injected directly into the central nucleus of the amygdala. The research outlined in this application will investigate the interactions of stress and the anxiety-like state produced by withdrawal from cocaine. The studies will determine if heightened anxiety leads to increased susceptibility to stress-induced relapse to cocaine-seeking behaviors using the reinstatement to cocaine place preference model in the rat. The anatomical site of action of delta opioid receptor agonists in relieving withdrawal-induced anxiety will be determined with a focus on the extended amygdala. As anxiety and the negative affective state that occur during cocaine withdrawal can precipitate relapse, the proposed research will determine if delta opioid receptor agonists can prevent stress-induced reinstatement. Additional studies will begin to elucidate the cellular and molecular mechanisms that are involved in anxiety-like states produced by cocaine withdrawal and the mechanism through which delta opioid receptors are producing their beneficial actions. The focus of these studies will be on the interactions of delta opioid receptors with corticotrophin releasing factor and noradrenergic transmission. The overall objectives of the proposed research are to determine the role of anxiety states in stress-induced relapse to cocaine-seeking behaviors and to elucidate the neural substrates underlying anxiety produced by withdrawal from repeated administration of cocaine. The significance of the proposed research is the establishment of a novel target for the prevention of relapse and the elucidation of the functional role of delta opioid receptors in the extended amygdala in modulating the negative effects of cocaine withdrawal. Dysregulation of the delta opioid system following chronic cocaine use may play a critical role in abnormal responsiveness to stress and the long-lasting vulnerability to relapse. PUBLIC HEALTH RELEVANCE: Anxiety produced by withdrawal from repeated cocaine use can precipitate relapse to drug-seeking and drug-taking behaviors, and the prevention of relapse is at the core of efforts to treat drug addiction. The proposed research will investigate the mechanisms of cocaine withdrawal-induced anxiety, the interactions of stress with anxiety-like states, and the potential utility of a delta opioid receptor drug to reduce anxiety and preven relapse. The overall goal of this work is to critically establish the delta opioid receptor as a noel target to treat anxiety during cocaine withdrawal and to prevent stress-induced relapse to addictive behaviors.